PT99398B - METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING TRICYCLIC COMPOUNDS WITH IMMUNOSUPPRESSOR ACTION - Google Patents

Abstract

A pharmaceutical emulsion composition or solution composition in an organic solvent containing a compound represented by the following chemical formula and having immunosuppressive activity is disclosed: <CHEM> <IMAGE>

Description

The present invention relates to pharmaceutical compositions containing a compound or a pharmaceutically acceptable salt thereof represented by the general formula I, described below, which is considered to exhibit immunosuppressive activity. More particularly, it relates to compositions in the form of an emulsion which maintain a stable emulsified state in a solution of physiological sodium chloride, solution of injectable glucose, water, fruit juice or other medium and thus can be applied. be administered by intravenous, intramuscular injection, local administration such as, for example, in eye drops, as well as in various forms of administration including oral or rectal administration, or to compositions in the form of a solution in an acceptable organic solvent under the From a pharmaceutical point of view, they are stable in liquid form in themselves, show less resistance to administration as oral compositions and have satisfactory absorbability in the digestive tract.

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BACKGROUND OF THE INVENTION

The compounds represented by general formula I and their pharmaceutically acceptable salts are known as substances that exhibit immunosuppressive activity (see Japanese patent Laid-Open Sho

61 (1976) -148181 and the European patent Laid-Open

NQ 0323042), and its application in various medical areas, including organ transplantation, such as heart, liver, kidney, bone marrow, skin, cornea, lung, pancreas, small intestine, muscles, nerves and limbs is expected:

where the vicinal pairs and 1 ^, R ^ and R ^ and Rg represent

or each form independently two vicinal hydrogen atoms or a second bond between the adjacent carbon atoms to which they are attached, respectively; and in addition to the meanings defined before

R ₂ represents an alkyl group;

Ry represents a hydrogen atom or a hydroxy group and optionally protected or alkyloxy or R? and R4, taken together, represent an oxo group;

Rg and Rg each independently represent a hydrogen atom or a hydroxy group;

^R 10 represents a hydrogen atom or an alkyl group, optionally comprising one or more hydroxy group (s) as a substituent (s), alkenyl possibly having one or more hydroxy group (s) as a substituent (s) or alkyl containing as an substituent an oxo group;

X represents an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or -CH ₂ O-;

Y represents an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or a group of general formula -N-NR-qR -] ^ ^or “N-OR - ^^ ⁱⁿ Q ^{ue R} 11 ^{and R} 12 ^{re resent} P am are each independently a hydrogen atom or an alkyl, aryl or tosyl;

^R 13 ' ^R 14' ^R 15 ' ^R 16 * ^R 17 * ^R 18' ^R 19 * ^R 22 ^{and R} 23 ^re P ^represent > each, independently, a hydrogen atom or an alkyl group;

R £ q and R22. each independently represent an oxo or C4 Oa (hydrogen atom) or hydrogen atom) group, respectively, wherein R2Q _to ^and ^ 21a each independently represent a hydroxy, alkoxy or OCI ^ OCE group ^ C ^ OCHg or R-2]. _a represents a protected hydroxy group; additionally, I <20a ^{and R} 21a may represent, taken together, oxygen atoms in an epoxide nucleus;

n represents an integer from 1 to 3; and in addition to the meanings defined before

Y, R- ^ θ and R ^ considered together with the carbon atoms to which they are attached, represent a pentagonal or hexagonal heterocyclic nucleus

, 7 *

.¾ saturated containing a nitrogen, sulfur or oxygen atom and having as one substituent (s) one or more group (s) chosen from alkyl groups, possibly having one or more hydroxy groups (s) as a substituent ( s), hydroxy, alkyloxy, benzyl or -C ^ SeCCgE ^).

These compounds of formula I and their pharmaceutically acceptable salts are prepared in the manner described in the two aforementioned patents. In particular, macrolides, which are prepared by fermentation of Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakushimaensis Νθ 7238 (FERM BP-928), are referenced by FR-900506, FR-900520, FR-900523 and FR-900525.

SUMMARY OF THE INVENTION

The compounds of general formula I and their pharmaceutically acceptable salts (here the term compounds of general formula I are represented to represent them) are less soluble in water and, therefore, when used as a pharmaceutical solution they can be considered as solubilized with the aid of a commonly used water solubilizing agent, such as ethanol or polyethylene glycol.

However, a pharmaceutical solution prepared by the aforementioned means can sometimes cause crystallization of the compound of general formula I when it is diluted with a body liquid in the applied portion and causes a reduction in the bioavailability of this compound of general formula I.

The present invention addresses the reported situations and it is an objective of this invention to provide pharmaceutical compositions, in particular emulsions or solutions in organic solvent, which do not cause the compound of formula I to crystallize when in contact with body fluids.

The pharmaceutical compositions according to the present invention contain as an active component a compound of formula I mentioned above, an emulsifying agent acceptable in the pharmacy or an oil phase component and particularly an oil-in-water (0 / A) emulsion or a its composition in solution in an organic solvent.

I

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 graphically illustrates the variation in blood concentration after oral administration to rats, determined according to Example 5, described later.

-7 DETAILED DESCRIPTION

The following are details for the various definitions used for general formula I, appropriate examples and illustrations which are explained in detail.

The lower designation used in this description means, unless otherwise indicated, a group with 1 to 6 carbon atoms.

J

Preferred examples of alkyl groups are aliphatic hydrocarbon residues, straight or branched chain, for example, a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, etc.

Preferred examples of alkenyl groups are aliphatic hydrocarbon residues, straight or branched, with a double bond, for example, lower alkenyl groups, such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, etc.

Preferred examples of aryl groups include, for example, phenyl, tolyl, xylyl, cumenyl, mesity, naphthyl, etc.

Preferred protecting groups in protected hydroxy groups are 1-lower (lower) -thioalkyl groups such as lower alkyl- (lower) -thiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butyl. thiomethyl, isobutylthiomethyl and hexylthiomethyl, preferably (C1 - C4) alkyl groups, thiomethyl, more preferably the methylthiomethyl group; tris substituted silyl groups, such as a trialkyl (lower) -silyl group, for example, trimethylsilyl, triethylsilyl, tributylsilyl, and tert.-butyldimethylsilyl or tri-tert.-butylsilyl; or (lower) alkyl-diarylsilyl, for example, methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl and tert.-butyldiphenylsilyl; more preferably for the trialkyl- (C ^-C ^) - silyl groups and (C ^-C ^) alkyl diphenylsilyl groups, more preferably for the tert.-butyldimethiisylyl and tert.-butyldiphenylsilyl groups; or an acyl group, such as an aliphatic or aromatic acyl group derived from a carboxylic acid, a sulfonic acid or a carbamic acid, or an aliphatic acyl group having an aromatic group as a substituent.

Examples of aliphatic acyl groups are lower alkanoyl groups, optionally containing one or more suitable substituents, such as carboxy groups, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl and carboxyhexanoyl; cycloal groups

lower (lower) -alkoxyalkyl, optionally containing one or more substituents, such as a lower alkyl group, for example, the cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxycyrethyl, mentyloxypropionyl, mentyloxypropyl, mentyloxypropane and hexyloxypropane; a camphorsulfonyl group or a (lower) alkyl-carbamoyl group comprising one or more substituents, such as an optionally protected carboxy group, for example, carboxy-(lower) alkyl-carbamoyl, such as, for example, the carboxymethylcarbamoyl, carboxyethylcarbamoyl groups, carboxypropylcarba moilo, carboxybutylcarbamoyl, carboxypentylcarbamoyl and carboxyhexylcarbamoyl, carboxy-lower (lower) -carbamoyl groups, such as trialkyl (lower) -silyl-alkoxy (lower) -carbonyl-alkyl- (lower) -carbamoyl groups , trimethylsilyl-methoxycarbonylethylcarbamoyl, trimethylsilyl-ethoxycarbonylpropylcarbamoyl, triethylsilyl-ethoxycarboxylpropylcarbamoyl, tert ^ -butyldimethylsilyl-ethoxycarbonylpropylcarbamoyl and trimethylsilyl-propoxycarbonylbutyl, etc.

Examples of aromatic acyl groups are the aroyl groups possibly containing one or more suitable substituents, such as. nitro group, for example, benzoyl, toloyl, xyloyl, naphthyl, nitrobenzoyl, dinitrobenzoyl and nitronaphtoyl; or an arenesulphonyl group possibly containing appropriate substituents, such as halogen atoms, for example, benzene sulphonyl, toluene sulphonyl, xylene sulphonyl,

-10naphthalene sulfonyl, fluorobenzene sulfonyl, chlorobenzene sulfonyl, bromobenzene sulfonyl and iodobenzene sulfonyl.

Examples of aliphatic acyl groups containing an aromatic group as a substituent include lower aralkanoyl groups possibly containing one or more substituents, such as lower alkoxy or trihalo-lower alkyl groups, for example, phenylacetyl, phenylpropionyl, phenylbutyryl,

2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl and 2-trifluoromethyl-2-propoxy-2-phenylacetyl.

The acyl groups most preferred among the aforementioned acyl groups are C - ^ - C ^ alkanoyl groups possibly containing a carboxy group, C (-Cg) cycloalkoxy - C ^ -C ^ alkanoyl group, containing two alkyl groups C ^ -C ^ in the cycloalkyl group, camphorsulfonyl groups, carboxy (C1-C4) -carbamoyl groups, trialkyl (C ^ -C ^) -alkylalkoxy (C - ^ - G ^) -carbonylalkylKC - ^ - C ^ j- carbamoyl, benzoyl groups possibly having one or two nitro groups as a substituent, benzene sulfonyl groups having a halogen atom or a C ^ -C ^ phenyl alkanoyl group containing a C ^ -C ^ alkoxy group and tri groups halo C ^-G ^alkyl. Among these groups, the most preferred groups are, for example, the groups acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, nitrobenzoyl, iodobenzene sulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.

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- Preferred examples of heterocyclic groups with a pentagonal ring or hexanol containing nitrogen, sulfur and / or oxygen atoms include the pyrrolyl and tetrahydrofuryl groups.

The pharmaceutically acceptable salts of the compounds of formula I include conventional non-toxic pharmaceutically acceptable salts, such as salts of organic or inorganic acids or bases, for example, an alkali metal salt such as a salt of sodium or a potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, and an ammonium salt or an amine salt, such as a triethylamine salt or an N salt -benzyl-N-methylamine.

With regard to the compounds of the general formula I of the present invention, they may have one or more conformations or stereoisomeric pairs, such as optic isomers or geometric isomers, due to the presence of an asymmetric carbon atom and a double bond, and these conformations or isomers are also within the scope of the present invention.

The emulsifying agent used in the present invention will also be described.

As an emulsifying agent, it is preferred to use natural or synthetic pharmacy-acceptable emulsifying agents. Among these, various emulsifying agents of

animal or vegetable origin as natural emulsifying agents including, for example, egg yolk lecithin, soy lecithin or their hydrogenation products, phosphatodyl choline, phosphatidylserine, sphingomyelin, gum arabic or gelatin without any particular restriction. Cationic, anionic, non-ionic or other surfactants can also be used as synthetic emulsifying agents. Nonionic surfactants are particularly preferred and their typical examples include castor oil type surfactants, preferably HCO (polyethylene-hardened castor oil) and more preferably, HCO-60, HCO-50 and HCO- 40 (registered trademark, prepared by Nikko Chemicals Co., respectively) with a view to a long storage period. In addition to the examples cited above, derivatives of polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, derivatives of glycerin fatty acid esters such as glycerin monocaprylate and derivatives of fatty acid and polyoxyethylene esters can also be used , such as polyoxyethylene 40 monostearate, mono or diglycerides of medium chain fatty acids (eg mono or diglycerides of fatty acids with 6 to 12 carbon atoms, such as caprylic acid monoglycerides, caprylic acid diglycerides and diglycerides capronic acid) and polyoxyethylated glycerides, such as polyoxyethylated oleic acid glycerides.

-13->

The aforementioned emulsifying agents are used as primary emulsifying agents and the eventual use of an auxiliary emulsifying agent is also included within the scope of the present invention. There is no particular restriction for all types of auxiliary emulsifying agents and their typical examples include, in particular, cholesterol, agar, magnesium hydroxide, methyl cellulose or pectin. For both agents, primary emulsifier and auxiliary emulsifying agent, each of the types of exemplified emulsifying agents can be used in combination, respectively.

With respect to the oil phase component used in the present invention, all those pharmacy-acceptable components can be used and their typical examples include, but are not limited to, vegetable oils, (for example, soybean oil, sesame oil, cottonseed oil, olive oil, safflower oil, corn oil, rapeseed oil, peanut oil, etc.); medium chain fatty acid triglycerides (for example, fatty acid triglycerides with 6 to 12 carbon atoms, (for example, caprylic acid, capronic acid or wooluric acid), such as Panasate 800, 810, 1000, 1200 , prepared by Nippon Yushi Co.); liquid hydrocarbons (for example liquid paraffin, squalene and squalane), which can be used in combination.

The pharmaceutical compositions according to the present invention contain the components mentioned above. In particular, a fine emulsion can be prepared in the manner described below in the typical examples in the case of the use of egg yolk lecithin, as an emulsifying agent and using soybean oil as a component of the oily phase, in such a way that very stable pharmaceutical compositions containing the compound of general formula I.

On the other hand, in the case of preparing pharmaceutical compositions in the form of a solution in an organic solvent, according to the present invention, any of the organic solvents can be used provided that they dissolve the compound of general formula I or an acceptable salt thereof in pharmacy, with ethanol being most preferred. In this case, the preferred emulsifying agent may include a polyoxyethylene-hardened castor oil, such as HCO-60, or a synthetic emulsifying agent, such as polyoxyethylated glycerides, (for example, glycerides polyoxyethylated oleic acid).

As a component for the preferred oil phase, medium chain fatty acid triglycerides can be mentioned.

In this case, the compound of general formula I is dissolved in a solvent mixture containing an organic solvent and a medium chain fatty acid triglyceride or a compound of general formula I is first dissolved in an organic solvent

to which the medium chain fatty acid triglyceride is added, then the emulsifying agent is added and mixed until homogeneity is obtained. It is intended for the synthetic emulsifying agent that the medium chain fatty acid triglyceride forms an emulsion in contact with a digestive solution to improve the absorption of the compound of general formula I. The medium chain fatty acid triglycerides have excellent solubility for the compound of general formula I when compared to the long chain fatty acid triglycerides (eg olive oil), but are not miscible with the synthetic emulsifying agent and cannot provide a homogeneous pharmaceutical solution. In view of the above, an organic solvent is used together, with ethanol being particularly preferred, to allow medium chain fatty acid triglyceride and synthetic emulsifying agent to mix homogeneously and reduce the viscosity of the total solution, facilitating the administration (easy usability) of the pharmaceutical composition.

In addition to the components described above, agents that control osmotic pressure that correspond to the part of the organism to which the composition is applied can be used together, this aspect also falling within the scope of the present invention. These osmotic pressure controlling agents can include, for example, a sugar alcohol such as glycerin, sorbitol, inositol, xylitol and mannitol. If necessary, antiseptic agents (for example,

example, benzalkonium chloride, various types of paraoxybenzoates, benzethonium chloride and chlorobutanol).

As mentioned above, the compositions of the present invention are pharmaceutical compositions that contain a compound of general formula I, the emulsifying agent and the oil phase component as essential components and the content of each of these essential components should now be explained. Advantageously, the content of the compound of general formula I will be fixed according to the place where the composition is to be applied. The recommended content is between 0.05 and 50 mg / ml for intravenous injection, between 1 and 50 mg / ml for intramuscular injection, between 0.1 and 50 mg / ml for eye drops and between 0.1 and 50 mg / ml for oral administration. The component can be diluted in aqueous media, for example, water, sodium chloride saline, glucose solution for injection, fruit juice or milk, according to the administration for which the composition is intended, so that the concentration is lower than the values previously indicated.

There is no special restriction on the mixing ratio of the oil phase component in these pharmaceutical compositions, but it is preferred that the oil phase component be mixed in the composition in the form of an emulsion in a proportion between 5 7 and 50 7, preferably between 5 7 and 20 7 (w / w).

Also for the content of the emulsifying agent, in the case of an injectable composition or eye drops, a value of between 0.5 and 50 parts by weight is preferred, more preferably between 1 and 30 parts by weight and even more preferably between 2 and 20 parts by weight based on 100 parts by weight of the oil phase component used.

In the case of an oral composition, 10 to 400 parts are used, preferably 50 to 200 parts by weight and more preferably 80 to 120 parts by weight, based on 100 parts by weight of the components of the oil phase.

Also, in the case of a composition in the form of a solution in an organic solvent the amount of organic solvent used must be between 0.002 and 2 ml, preferably between 0.01 and 1 ml and particularly preferably between 0.02 and 0 , 5 ml with respect to 1 mg of compound of formula I.

Pharmaceutical compositions can also be obtained when the compounds described in the documents referred to below are used, such as in European patent EP-A-353678, Japanese patent application NQ HEI 2 (1990) -74330, PCT / GB90 / 01262, European patent EP-A-413532, PCT / JP91 / 00314, British patent application NQ 9012963.6, British patent application NQ 9014136.7, British patent application NQ 9014681.2,

British patent application NQ 9014880.0, British patent application NQ 9014881.8, British patent application NQ 9015098.8, British patent application N2 9016115.9, British patent application N2 9016693.5, European EP patents -A-323865,

EP-A-349061, EP-A-358508, EP-A-364031, EP-A-364032, EP-A-378317,

EP-A-378320, EP-A-378321, EP-A-388153, EP-A-396399, EP-A-396400,

EP-A-399579, EP-A-403242, EP-A-428565, EP-A-356399, EP-A-402931 and EP-A-427680 and in British patent GB 2225576A.

EXAMPLES

EXAMPLE 1

Compound of general formula I in which:

R _p ^R 2 ' ^R 8 ^{and R} 23 each have a hydrogen atom;

Ry and Rg each represent a hydroxy group;

^R 10 represents an allyl group;

R ₁₄ , K.

methyl group;

16 '17' ± 8 ' ^R 19 ^and ^ 22 ^re P ^resent > each one

R2q is (R ^ Oa '^ h hydrogen ^atom) and P ^{re resents a} methoxy group;

R <2p represents (la R ^ '^ h hydrogen ^atom) and P ^{re resents a} hydroxy group;

X and Y each represent an oxygen atom, n represents 2;

R ^ and R ^ form a second bond between the neighboring carbon atoms to which they are attached;

R5 and Rg form a second bond between the neighboring carbon atoms to which they are attached;

and the symbols represented by the solid lines and the dashed lines represent a double bond, being used in a free form. The compound exhibits excellent suppressive activity and is referred to herein by EK506.

Mix 0.5 g of FK506 with 200 g of soy oil and 24 g of egg yolk lecithin and heat to about 80 ° C to obtain a homogeneous solution.

EXAMPLE 2

An aqueous solution of 2.5 X glycerin (1.6 liters) is added, under heating to a temperature between 70 ° C and 80 ° C, to the homogeneous solution obtained in Example 1 and emulsified by stirring for 30 minutes at 6000 revolutions per minute, in a TK homomixer (manufactured by Tokushu Kika Kogyo Co., Japan), while maintaining the temperature between 70 ° C and 80 ° C. Then, it is emulsified at a temperature between 75 ° C and 80 ° C in a Manton Gaurin homogenizer (manufactured by Manton Gaurin Co., -2

USA) under a pressure of 316 kg / cm (4500 psi) and with a number of passages of 10 times. After cooling the emulsion to room temperature, distilled water was added to make the total amount of 2 liters.

EXAMPLE 3

After stirring 0.5 g of FK506 in 100 ml of a commercial fat emulsion for intravenous injection (trade name, Intralipid 10 X; manufactured by Ohtsuka Seiyaku) overnight at room temperature, filter through a 0.45 filter. ytm from Milipore Co. to obtain a fat emulsion for intravenous injection containing FK506 at a concentration of 0.293 mg / ml.

-21EXAMPLE 4

After preparing a solution (example of comparison), suspension (example of comparison) and emulsion (Example 3) they are compared in relation to their transferability in the eye of the rat, obtaining the results shown in Table I. As shown in Table , emulsion 3 shows excellent transferability in the eye of the rat and it is considered that the emulsion according to the present invention does not cause deposition of the active component when in contact with the body liquid. The conditions of administration are 5 drops, about 10 µl, and the data shown in Table I show the concentration in each tissue one hour after administration (n = 4, mean value + standard deviation).

-2 ^ TABLE 1

Solution Suspension (particle size: 6.5 yjtfn) Emulsion (fat emulsion for intravenous injection) Preparation FK506 0.05 mg 1 mg 0.293 mg HPMC 3.5 3.5 - D-mannitol - - - Polysorbate 80 10 - - Hydrogen sodium phosphate 0.184 0.184 - Sodium dihydrogen phosphate 15.47 15.47 - Phosphoric acid 0.0032 ' 0.0032 - Sodium chloride 2.88 2.88 - Benzal chloride- 0.2 0.2 conio 0.2 0.2 - Soy oil - - 100 Egg yolk lecithin - - 12 Glycerin - - 25 Distilled water up to 1 ml up to 1 ml up to 1 ml Corneal Transphere 192.9 + 48.5 141.3 + 21.7 762.8 + 60.6 skill in the eye Retina 2.6+ 1.8 2.5+ 0.7 26.2+ 3.2 mouse [ng / choroidal liquid of (g)] crystalline n. d. n. d. 1.9+ 0.7

EXAMPLE 5

The emulsion prepared according to Example 3 containing FK506 and a solution prepared by suspending 30 mg of fine powder FK506 in 100 ml of sodium chloride saline solution (FK506 suspension with 10.3ytf <m size particles are administered by orally to each of the rats and the oral absorption of FK506 is evaluated.

The absorption experiment is carried out according to the following method.

Male rats, SD series, with eight weeks of age and 300 g of body weight, deprived of food the previous day, are fixed on the posterior part and are administered orally and through a probe 1 mg / kg, using four rats per sample.

From the femoral aorta connected to a cannula, 0.2 ml of blood is collected at specific times (30 minutes, 1, 2, 4, 8 and 24 hours) and the blood samples are kept refrigerated and with the addition of heparin to 1 Z. After thawing, the FK.506 concentration of whole blood is determined using an enzyme-linked immunoassay.

The results are shown in Figure 1. As seen in the Figure, it can be seen that, in the case of the emulsion of the present invention, maximum absorption for FK506 is obtained more quickly and with a higher concentration in the blood than that obtain with the administration of the suspension.

EXAMPLE 6

FK506 2 mg

HCO-60 100 mg

Ethanol 0.2 ml

Medium chain acid triglyceride up to 1 ml (Migriol 812 (trade name) prepared by Huls AG)

EXAMPLE 7

Stability during storage of the composition as an ethanol solution obtained in Example 6 (Table 2) is examined.

-25 TABLE 2

PHARMACEUTICAL FORM: composition in the form of a solution in ethanol

LOT N2: Example 6

PREPARATION

FK506 2 mg

HCO-60 100 mg

Absolute ethanol 0.2 ml

Medium chain fatty acid triglyceride to 1 ml

Storage conditions Percentage (Z) of FK506 Initial ? 100.0 (4.87) 80 ° C 3 days 89.2 5 days 84.3 10 days 75.9 (4.42) 60 ° C 10 days 95.3 17 days 94.2 1 month 88.8 (4.45) 40 ° C 1 month 99.2 (4.77) 3 months 96.4 (4.54) activation energy (kcal / mole) 22.9 Tg _O k expected value at temperature of 25 ° C 4.4 years

The values in parentheses represent the pH values for the solution diluted about 5 times with water.

-26Λ »

As shown in Table 2, it is confirmed that it is possible to conserve the ethanol solution obtained according to Example 6 for a long period.

EXAMPLE 8

FK506 2 mg

420 mg polyoxyethylated oleic acid glyceride (labrafil, trade name M1944CS, manufactured by Gatte fassé Co.)

400 mg medium chain fatty acid glyceride

Ethanol up to 1 ml

A composition is prepared, containing the components mentioned above, capable of forming an emulsion after application, according to a conventional method.

EXAMPLE 9

FK506

Caprylic acid monoglyceride mg

0.2 ml

-27 Medium chain fatty acid triglyceride 0.6 ml

Ethanol up to 1 ml

A composition is prepared, containing the components indicated above, capable of forming an emulsion after use, according to a conventional method.

EFFECT OF THE INVENTION

As the pharmaceutical compositions according to the present invention do not cause crystallization of the active components when in contact with body fluids, it has been confirmed that said compositions have excellent bioavailability and stability. In addition, the compositions according to the present invention also have the advantage of being pleasant to the palate of children, making it easy to adjust the dosage.

The pharmaceutical compositions according to the present invention, due to the pharmacological activity of the tricyclic compounds of general formula I, are usable for the treatment and prevention of diseases mediated by the immune system, such as organ and tissue transplants such as the heart, kidney , liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limbs, muscle, nerves, etc .; diseases due to bone marrow transplantation caused in the host; diseases of

autoimmunity such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc .; and infectious diseases caused by pathogenic microorganisms.

In addition, tricyclic compounds of general formula I are also useful for the treatment and prophylaxis of inflammatory and hyperproliferative diseases of the skin and cutaneous manifestations of diseases linked to the immune system, such as psoriasis, atopic dermatitis, contact dermatitis and also eczematous dermatitis, seborrhea, Lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, Lupus erythematosus, acne and Alopecia areata; various diseases of the eye such as autoimmunity diseases, etc., (for example, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, corneal epithelial dystrophy, corneal leukoma, eye pemphigus, ulcer of the eye Mooren, scleritis, severe scleritis, ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.); obstructive airway diseases, including asthma (for example, asthmatic bronchitis, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or severe asthma (eg, late asthma and airway hyperactivity), bronchitis, etc .; inflammation of mucous membranes and blood vessels, such as gastric ulcer, vascular damage caused by skeletal diseases and thrombosis, skeletal disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal injuries associated with burns, mediated diseases by leukotriene B ^; intestinal inflammations and allergies such as Coelic disease, proctitis, eosinophilic gastroentritis, mastocytosis, Crohn's disease and ulcerative colitis; allergic diseases arising from food with remote symptomatic manifestations of the gastrointestinal tract, for example, migraine, renitis and eczema; kidney diseases such as interstitial nephritis, Goodpasture's syndrome, uremic-hemolytic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillian-Barré syndrome, Ménière's disease and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; blood disorders such as aplasia of red blood cells, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerithroplasia; bone diseases like osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, allergic sensitivity to light and cutaneous T-cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adipose; eosinophilic fasciitis; perio.dontal disease such as lesions of the gums, periodontium, alveolar bone, bone substance dentis; nephrotic syndrome such as glomerulonephritis; male alopecia and senile alopecia; dystrophy

-30 muscle; Sezary syndrome and pyoderma; diseases induced by active oxygen, for example, organic lesions, such as lesions of organs with ischemic reperfusion (for example, heart, liver, kidney, digestive tract), which occur in the guard period, in transplantations or ischemic diseases (thrombosis, cardiac infarction); intestinal diseases such as shock by endotoxins, pseudomembranous colitis, colitis caused by drugs or radiation; kidney diseases such as acute ischemic kidney failure, chronic kidney failure; lung diseases such as oxygen toxinosis of the lung or drug (eg, paracort, bleomycins), lung cancer, pulmonary emphysema; eye diseases such as cataracts, siderosis, retinitis, pigment, senile macular degeneration, vitreous scabs, corneal burns caused by alkaline substances; dermatitis, such as erythema multiforme, bullous I A linear dermatitis,

S dermatitis caused by cement; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), age, carcinogenesis, carcinoma metastasis, hypobaropathy, diseases caused by histamine or C4 leukotriene release, etc. .

In addition, the tricyclic compounds of general formula I exhibit liver regeneration activity and / or activities that stimulate hepatocyte hypertrophy and hyperplasia.

Therefore, they are useful for the treatment and prevention of liver diseases, such as immunogenic diseases (for example,

chronic autoimmune liver disease such as the group of diseases including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (for example, toxin necrosis, viral hepatitis, shock or anoxia), hepatitis B virus , non-A / non-B hepatitis, cirrhosis and liver failure such as fulminant liver failure, late liver failure, and acute-chronic liver failure (acute liver failure in situations of chronic liver disease).

I

In addition, the tricyclic compounds of general formula I are usable for several diseases due to their useful pharmaceutical activity, such as increased activity of the chemotherapeutic effect, prevention or treatment of cytomegalovirus infections, anti-inflammatory activity, etc.

Claims (4)

1.- Process for the preparation of pharmaceutical compositions in the form of an organic solution or type 0 / A emulsion containing, as an active ingredient, a tricyclic compound of general formula / -33- (I) 5 “1 · in which / the vicinal pairs R ^ and R ^> Rg and R ^ and R ^ and Rg each independently represent or form two vicinal hydrogen atoms or a second bond between the adjacent carbon atoms to which they are attached , respectively; and in addition to the meanings defined above; R ₂ represents an alkyl group; R ₇ represents a hydrogen atom or an optionally protected hydroxy group or alkyloxy or R ·? and R-, taken together, represent a group / -34 Rg and Rg each independently represent a hydrogen atom or a hydroxy group; R ^g represents a hydrogen atom or an alkyl group, optionally comprising one or more hydroxy group (s) as a substituent (s), alkenyl possibly containing one or more hydroxy group (s) as a substituent (s) or alkyl having an oxo group as a substituent; X represents an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or -CH2 ^O -; Y represents an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or a group of the general formula -N-NR- ^ R. ^ or -N-OR ^ g. wherein R ^ and R ^ each independently represent a hydrogen atom or an alkyl, aryl or tosyl group; ^R 13 ' ^R 14' ^R 15 ' ^R 1o' ^R 17 ' ^R 18' ^R 19 ' ^R 22 ^{and R} 23 ^rspr each independently represent a hydrogen atom or an alkyl group; R _2q and R _o ^ each independently represent an oxo group or (R _2Qa , hydrogen atom) or ( ^R 21a '^ ^{01110 á and} hydrogen), respectively, at / -35., ..... wherein R ^, Q and ^R 21a _to R ^{resen re} tam, each, irrespective hydroxy, alkoxy or OCH ₂ OCH ₂ CH ₂ OCH ₃ or R ₂ i _a represents a protected hydroxy group; in addition, R „ _n and R_ may represent, taken together, oxygen atoms in an epoxy nucleus; n represents an integer from 1 to 3; and in addition to the meanings defined above; Y, e & 23 'taken together with the carbon atoms to which they are attached, represent a pentagonal or hexagonal heterocyclic nucleus. optionally saturated containing an azo atom, sulfur or oxygen and one or more selected group (s) between alkyl groups, possibly comprising one or more hydroxy group (s) as a substituent (s), hydroxy, alkyloxy, benzyl or -CH ₂ Se (C _g H ₅ ); or a pharmaceutically acceptable salt, with immunosuppressive action, characterized by the fact; (a) mixing the tricyclic compound or its salt with a pharmacy-acceptable emulsifying agent and oil; or (b) dissolving the tricyclic compound or a salt, the emulsifying agent and the oil acceptable in the pharmacy in an organic solvent also acceptable in the pharmacy; ef - ³⁶ «.« · »(c) adding an aqueous medium to the suspension obtained in (a) or to the organic solution obtained in (b); the amount of active ingredient may vary between 0.05 and 50 mg / ml. 2. Process according to claim 1, characterized in that an oil-in-water emulsion is obtained containing the suspension prepared in (a). 3. A process according to claim 2, characterized in that a natural emulsifying agent is used as a pharmaceutically acceptable emulsifying agent. 4. Process according to claims 2 and 3, characterized in that vegetable oil is used as an acceptable oil phase in the pharmacy. > 5. A process according to claim 1, characterized in that an organic solution containing the suspension prepared in (a) is obtained. 6. A process as claimed in claim 5, characterized in that a medium chain fatty acid triglyceride is used as a pharmaceutically acceptable oil phase. 7. Process according to claim 1, characterized in that an oil-in-water emulsion is obtained containing the organic solution prepared in (b). 8. A process according to claims 5 to 7, characterized in that ethanol is used as an acceptable organic solvent in the pharmacy. 9. A process according to claim 8, characterized in that a synthetic emulsifying agent is used as a pharmaceutically acceptable emulsifying agent. 10. A process according to claim 9, characterized in that poly (oxyethylated) glyceride is used as the synthesis emulsifier. 11. Process according to claims 1 to 10, characterized in that a tricyclic compound of general formula I is used as the active ingredient in which the vicinal pairs Rg and eR- and R _g each form, independently, one second connection between the carbon atoms to which they are attached; Rg and Rg3 each independently represent a hydrogen atom; R _g represents a hydroxy group; R- ^ θ represents a methyl, ethyl, propyl or allyl group; X represents (atom of hi -38 hydrogen, hydrogen atom) or an oxo group; Y represents a R. oxo group; each of the symbols, R ^^, ^R 16 ' ^R 17' ^R 18 'and R ^ 2 represents a methyl group; ^{and R} 21 ^re P ^resentam 'each independently ^(R 20a' hydrogen atom) or ^(R 2ia 'hydrogen atom) in which R 20a ^{and R} 21a ^re P ^resentam' spectively, hydroxy or alkyloxy or R2ia ^re P ^{is a} protected hydroxy powder; en represents the integer 1 or 2. 12. A process according to claims 1 to 11, characterized in that a tricyclic compound of general formula I is used in which R 1 represents a hydrogen atom or an optionally protected hydroxy group; X represents an oxo group; R ₂ Qa ^re P ^{has 11111} methoxy group and R ₂ i _a represents an optionally protected hydroxy group. 13.- Process according to claims 1 to 12, characterized in that it is used as a tricyclic compound of general formula I at 17-allyl-1,4-dihydroxy-12- [2- (4-hydroxy-3 -methoxycyclohexyl) -1-methyl-vinyl] -23,25-dimethoxy-13,19,21, 4 9 27-tetramethyl-11, 28-dioxa-4-azathricycle (22,3,1,0 *) octacos-18-ene-2,3,10,16-tetraone or 17-ethyl-1,14-di- hydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4- azatriciclo 4 9 (22 _< 3 «1 * O *) octacos-18-ene-2,3,10,16-tetraone.